Studies on patients with Alzheimer's disease (AD) using positron emission tomography show impaired brain glucose utilization as an early manifestation. We have identified a molecular mechanism involving mitochondrial and nuclear genetic systems of oxidative phosphorylation (OXPHOS) that may relate to this impairment. Post-mortem brains from AD patients showed 40% - 60% decreases in levels of mRNA for mitochondrial DNA (mtDNA) encoded - cytochrome oxidase (COX) subunits I, III and NADH-dehydrogenase subunit 1 as well as for nuclear DNA (nDNA) encoded F0F1-ATPase subunit in midtemporal cortex (association cortex showing reduced metabolism in life) not in the unaffected primary motor cortex (primary cortex comparatively spared), compared with control tissue. There was no difference in expression of the mitochondrial 12S rRNA (mitochondrial transcript) gene, nuclear lactate dehydrogenase subunit B (a marker of glycolytic metabolism) gene, nor of nuclear beta actin gene. COX enzyme activity was decreased by 34% in temporal association neocortex of AD brains as compared with control cortex. The question of whether the impairments in mitochondrial oxidative metabolism are a primary or secondary to other pathologic changes in AD remains to be answered. Direct cytochrome oxidase inhibition in the rat, induced by continuous infusion of sodium azide, resulted in neuronal death when combined with administration of a low dose of corticosterone.